Download Laboratory Newsletter | 2014

Human Genetics Laboratory
985440 Nebraska Medical Center
Omaha, NE 68198-5440
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Newsletter
for health care providers
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issue
page 1 ACOG recommends Prenatal Microarray
Recent recommendations have increased the use of microarray in the prenatal setting.
page 4 FISH for Non-Small Cell Lung Carcinoma (NSCLC)
Tiered FISH testing is recommended to detect abnormalities in ALK, ROS1, and RET.
page 6 A new approach to comprehensive gene panel testing
Next Generation Sequencing (NGS) combined with Deletion/Duplication Analysis allows
detection of both sequenced-based variations and intragenic copy number changes.
Human Genetics Laboratory Newsletter | Summer 2014
UNMC Human Genetics Laboratory
for health care providers
Prenatal Microarray
O
ur laboratory offers a wide
range of prenatal genetic testing
services, which include chromosome
analysis (karyotyping), fluorescence
in situ hybridization (FISH), and
microarray analysis. Historically,
chromosome analysis and FISH
have been the predominant assays
of choice for indications such as
advanced maternal age; abnormal
ultrasound findings; abnormal 1st,
2nd, or combined maternal serum
screening result; and a family
history of a genetic or chromosomal
abnormality. These tests continue to
provide practitioners and patients
with valuable diagnostic information
in the prenatal period.
More recently, the use of microarray
analysis in the prenatal setting has
steadily increased, at least partly as
a result of the joint opinion put forth
by the American College of Obstetrics
and Gynecology (ACOG) and the
Society of Maternal Fetal Medicine.
This opinion recommends the use
of microarray analysis when fetal
ultrasound anomalies are detected or
when a patient is undergoing invasive
prenatal diagnostic testing and
emphasizes that this analysis should be
made available to patients regardless
of maternal age.1
In the prenatal setting, our laboratory
uses a microarray platform designed
specifically for the detection of
submicroscopic deletions and
duplications in regions of known
clinical relevance. In addition, this
platform offers whole genome
coverage for accurate copy number
assessment and includes single
nucleotide polymorphisms (SNPs) for
enhanced detection of maternal cell
contamination. Results for this testing
are typically available within 1-2 weeks
of specimen receipt in the laboratory.
Please contact us for additional
information about the benefits of
Prenatal Microarray for your patients.
1 The use of chromosomal microarray analysis in prenatal diagnosis. Committee Opinion No. 581. American College of Obstetricians
and Gynecologists. Obstet Gynecol, 122:1374-1377, 2013.
Genetic Counselors Essential to Laboratory Mission
As part of our comprehensive services, the Human Genetics Laboratory team includes
licensed and board-certified genetic counselors to assist providers and their patients. Our
genetic counselors have current clinical experience as well as dedicated areas of expertise,
ranging from prenatal and postnatal genetics to oncology. Serving as a liaison between
providers and laboratory services, genetic counselors recommend indication-specific testing
strategies, request additional clinical information for improved testing and interpretation,
notify providers of STAT results, and discuss test results and pertinent management issues.
Our counselors look forward to interacting with you.
Human Genetics Laboratory Newsletter | Summer 2014
From the director
Our laboratory continues to provide diagnostic genetic testing services to clinicians across a number
of specialties, including pediatrics, obstetrics and gynecology, neurology, cardiology, genetic
medicine, medical oncology, and pathology. In addition, clinical geneticists and genetic counselors
continue to offer consultation in Omaha and across the state of Nebraska. Because genetic testing
is constantly evolving, our team remains committed to provider outreach and education and has
bolstered our ability to do so in a number of ways over the past year:
• We now have a dedicated marketing specialist who serves as a resource for providers.
• Our laboratory directors, genetic counselors, and marketing specialist routinely make personal
visits to clinics and hospitals.
• Our clinical genetics team has expanded their specialty clinics to include adult genetics, autism,
complex craniofacial, hereditary cancer, metabolism, neurosensory, and prenatal development.
• We have enhanced provider and patient educational materials, including prenatal and
postnatal testing booklets, hereditary cancer testing and oncology flyers, and patient brochures.
Newsletter
|
Summer 2014
This Newsletter is produced by
the Human Genetics Laboratory,
part of Munroe-Meyer Institute
at the University of Nebraska
Medical Center.
For additional printed copies,
or other information,
please contact:
Nicole (Nikki) Hackendahl
Marketing Specialist
402-559-6935
[email protected]
Human Genetics Laboratory
985440 Nebraska Medical Center
Omaha, NE 68498-5440
[email protected]
In addition, clinical and laboratory faculty and genetic counselors are always willing to provide formal
educational lectures for your staff. Please contact our marketing specialist, Nicole Hackendahl (see
left sidebar), if you would like more information about the educational materials available or if you
would like to schedule a formal meeting with one of our faculty.
Our dedicated and experienced technical staff is continually researching and developing new,
clinically-relevant genetic testing in order to improve the diagnostic yield for your patients. We have
expanded our test menu to include high resolution deletion/duplication analysis of clinically-relevant
genes to complement our sequencing panels. Over the past year, we also developed and validated
a hereditary breast cancer panel designed to detect abnormalities in six high-risk genes associated
with breast cancer, and I am pleased to announce that we are expanding this service to other
hereditary cancers (including colorectal, ovarian, uterine, endocrine, neuroendocrine, neurologic,
pancreatic, and renal) early this fall. We have also validated additional oncology fluorescence in situ
hybridization (FISH) probes for clinically relevant loci, such as IGK, IGL, ROS1, and RET. Please
continue to check our website for the most up-to-date test offerings and continue to communicate
your genetic testing needs to our laboratory team, as your requests serve as the basis for our future
assay developments.
Thank you for your ongoing loyalty and trust in our genetic services. We are honored to partner with
you in service to patients and remain committed to doing so with unparalleled accuracy, efficiency,
and compassion.
www.unmc.edu/geneticslab
Warren G. Sanger, Ph.D.
Director, Human Genetics Laboratory
Interim Director, Genetic Medicine
Munroe-Meyer Institute
University of Nebraska Medical Center
Newsletter | 2
FACULTY HIGHLIGHTS
R. Tanner Hagelstrom, PhD, MBA, FACMG
Jennifer N. Sanmann, PhD, MB(ASCP)CMCGCM
Dr. Tanner Hagelstrom is an Associate Director of the
Human Genetics Laboratory at the Munroe-Meyer Institute.
He is a Fellow of the American College of Medical Genetics
and Genomics (ACMG) and
is board certified in Clinical
Cytogenetics and Clinical
Molecular Genetics through
the American Board of Medical
Genetics and Genomics.
Following completion of a two year clinical cytogenetics
fellowship this June, Dr. Jennifer Sanmann joined the Human
Genetics Laboratory as an Associate Director. She is board
eligible in the subspecialty of
Clinical Cytogenetics through
the American Board of Medical
Genetics and Genomics.
Although her roles and
responsibilities in the laboratory
have changed over time, Dr.
Sanmann has been a member of
the Human Genetics Laboratory
team since 2005. She completed
both her doctoral and clinical
postdoctoral training under the
direction of Dr. Warren Sanger in 2012 and 2014, respectively.
Dr. Hagelstrom received his
PhD and MBA from Colorado
State University in 2007 and
2010, respectively. Following
a postdoctoral training at the
Translational Genomics Research
Institute in Scottsdale, Arizona, Dr. Hagelstrom completed
his Clinical Cytogenetics and Molecular Genetics fellowships
at the University of Colorado Anschutz Medical Center.
Dr. Sanmann began her academic appointment at UNMC
as an Assistant Professor of the Munroe-Meyer Institute on
July 1. She currently serves as a board member for the Great
Plains Chapter of the Clinical Laboratory Management
Association. Dr. Sanmann’s research focuses on understanding
the relationship between genotype and phenotype in both
the constitutional and oncology settings using a variety of
cytogenetic and molecular genetic techniques.
Dr. Hagelstrom joined the laboratory in July 2013 and
is currently an Assistant Professor of the Munroe-Meyer
Institute at UNMC. He serves on the ACMG Program
Committee, and his research interests focus primarily on
identifying unique genetic changes that can be utilized for
diagnostic purposes or treatment decisions in malignancies.
Tips & Tools:
Preauthorization of Genetic Testing
Due to the rapid advancements in genetics, a growing number of practitioners are utilizing genetic testing for the diagnosis and
medical management of their patients. Consequently, preauthorization for genetic testing has become increasingly prominent in
clinics and hospitals across the country. In order to aid practitioners in this preauthorization process, our laboratory has developed
specimen- and diagnosis-specific forms that query the information required for the determination of coverage and preauthorization.
The following preauthorization forms are available on the Human Genetics Laboratory website:
• prenatal
• pregnancy loss
• postnatal (peripheral blood)
• hematology / oncology
Upon request, our laboratory will obtain preauthorization for your patient’s genetic studies. Please contact our billing team with any
questions or concerns related to this process. 402.559.5070
FIND US ONLINE www.unmc.edu/geneticslab
Human Genetics Laboratory Newsletter | Summer 2014
Any FISH Necessary to Clarify Diagnosis, Clarified
We recently modified our Oncology Test Request Form to simplify the ordering process for
clinicians and their staff. There is an option on the form within Test Selection that, when
checked, authorizes our laboratory to perform any FISH necessary to clarify the patient’s
diagnosis. For ease, this option is now located directly below Chromosome Analysis.
p
 Chromosome Analysis
p
 Perform any FISH necessary to clarify diagnosis
p FISH [specify]:
FISH Analysis: NonLung cancer is the most common
cancer worldwide and is the leading
cause of cancer death in the United
States.1-2
By selecting the “any FISH necessary to clarify diagnosis” option on the test request form,
ordering providers eliminate any delay in testing that may occur while authorization is
obtained and fulfill the laboratory’s regulatory requirement for written orders without
disruption of your clinic or hospital for authorization.
Our laboratory staff will only add adjunct FISH when indicated by diagnosis or when needed
to clarify an abnormality observed by Chromosome Analysis (karyotyping). In addition, we
will always provide a fax notification when tests are added to keep the ordering physician
abreast of the pending studies.
Please note that this option does not replace the specified FISH test selection, which should
still be used in cases where the physician wants to order a specific FISH test at the time of
specimen collection. A current list of all of our available hematology, lymphoma, and solid
tumor FISH probes is available on our laboratory website.
p
 Chromosome Analysis
p Perform any FISH necessary to clarify diagnosis
p
 FISH [specify]: CLL Panel
ALK (2p23) Dual Color Breakapart Probe, positive
for rearrangement in a polyploidy population
Optimized microarray for subotimal specimens,
including solid tissue tumors
Our laboratory has recently obtained
the OncoScanTM microarray platform,
which has been designed to circumvent
the obstacles typically encountered
with these degraded specimens.
The Human Genetics Laboratory has performed
chromosomal microarray studies on a variety of sample
types since the technology’s infancy. However, historical
platforms have long been challenged to analyze
DNA of suboptimal quality, such as that from formalin
fixed paraffin-embedded (FFPE) tissues, which has
restricted genomic analysis on certain specimens.
This whole genome assay will detect
genomic dosage anomalies (deletions
and duplications) and copy-neutral
loss of heterozygosity at a resolution of
50-100kb in approximately 900 cancerrelated genes and at a resolution of
300kb throughout the remaining genomic
backbone. Thus, this platform is ideal
for the identification of diagnosis-specific
genetic profiles in solid tissue tumors.
Currently, the platform is being
utilized for research aimed at
Newsletter | 4
-Small Cell Lung Carcinoma (NSCLC)
Lung cancer is divided into two histologic subgroups: (1) non-small cell lung cancer (NSCLC), which accounts for more than 85% of
cases and can be subdivided into non-squamous carcinoma (including adenocarcinoma, large cell carcinoma, other cell types) and
squamous cell carcinoma and (2) small cell lung cancer, which accounts for the remaining ~15% of lung cancer cases.2 In recent years,
the understanding and knowledge of the pathogenesis of NSCLC, particularly adenocarcinoma, has grown exponentially and has led
to the discovery of novel acquired genetic abnormalities that allow for targeted therapies.
Several biomarkers have been identified in NSCLC that help drive therapy and predict treatment efficacy. These predictive biomarkers
include EGFR, HER2 (ERBB2), and BRAF mutations; ALK, ROS1, and RET rearrangements; and MET amplification.2 The NCCN
Guidelines for NSCLC recommend EGFR mutation testing and ALK gene rearrangement analysis for patients with adenocarcinoma;
large cell carcinoma; NSCLC not otherwise specified (NOS); or squamous cell carcinoma in never smokers, a small biopsy specimen,
or a specimen with mixed histology.2 The NCCN guidelines recommend subsequent consideration should be given to the other
genetic biomarker testing following EGFR and ALK as appropriate.
To meet clinical testing needs, our laboratory offers assessment of the ALK, ROS1, and RET loci using fluorescence in situ hybridization
(FISH). The FISH assay for each of these three loci is designed to detect rearrangement of the gene that, if present, is known to be
susceptible to targeted therapies. The ALK, ROS1, and RET FISH testing is typically performed on 4-6 µm sections prepared from
paraffin-embedded tumor tissue, and results are available within 3-5 days of specimen receipt. Please contact the laboratory for any
questions regarding this testing.
REFERENCES
1 World Health Organization. Cancer. Fact Sheet No 297. January 2013.
2 National Comprehensive Cancer Network (NCCN). Non-Small Cell Lung Cancer (Version 4.2014)
Education and Outreach
improving our understanding
of the genetic hallmarks of
various pediatric brain tumors.
The Human Genetics Laboratory was represented at the national American
College of Medical Genetics and Genomics (ACMG) meeting in Nashville
in March. The meeting provided a great opportunity for several of our
faculty and staff to learn about the
latest advancements in the field
and to reconnect with colleagues.
Additionally, this platform is being
validated for use in the clinical setting
(FFPE or otherwise suboptimal
specimens) and is projected to be
available for order in the fall of 2014.
In addition, the ACMG meeting
afforded our team the opportunity to
share our newest clinical test offerings
with attendees and to present our
latest research efforts in the postnatal
realm, which included the following:
If you would like more information
about how this assay may assist
with your research goals, or if you
would like additional information
as this assay transitions to a
clinical test offering, please
contact Dr. Sanmann for details.
[email protected]
• Clinical and Laboratory Collaboration: Team Approach to Next Generation
Sequencing Variant Interpretation (D.L. Bishay, et al.)
• Genetic Testing for Dilated Cardiomyopathy: Ethical Dilemmas Including
PSEN1 and PSEN2 (A.C. Carter, et al.)
• Hajdu-Cheney syndrome: patient with rare complex heart defect (L.J. Starr, et al.)
• Psychiatric Disease is Common and Undertreated in Ehlers-Danlos Syndrome
Hypermobile Type (E.T. Rush, et al.)
• Utility of Fluorescence In Situ Hybridization (FISH) to Confirm Copy Number
Changes Identified by Microarray (J.N. Sanmann, et al.)
2014 Human Genectics Laboratory ACMG booth.
Abstracts above available upon request.
Human Genetics Laboratory Newsletter | Summer 2014
A COMPREHENSIVE APPROACH
TO GENE PANEL TESTING
G
enetic changes that result in disease come in several different forms,
including sequence-based mutations (changes in the DNA at the basepair level) and intragenic deletions/duplications (copy number changes
within the target gene). Regardless of the type of disease-causing change
observed, these genetic aberrations often result in a similarly aberrant
protein product. Current technology does not allow for both sequence-based
variations and intragenic copy number changes to be detected reliably in
a single assay. Thus, comprehensive analysis of genes for disease-causing
aberrations typically requires a multi-assay approach.
In order to ensure comprehensive analysis of clinically-relevant genes of
interest, our laboratory recently added high resolution deletion/duplication
analysis for all of the genes that we have traditionally sequenced using
our next generation sequencing (NGS) technology. Therefore, we are able
to evaluate a panel of indication-specific genes for both sequence-based
mutations and small-scale deletions or duplications in a time- and costefficient manner. This combination of testing can be easily ordered on
our test request form by selecting the “comprehensive testing” box for
any of our panel tests. When comprehensive testing is selected, testing is
performed in a tiered manner to eliminate unnecessary costs to the patient.
The tiered approach for each indication-specific panel is outlined next to the
comprehensive testing selection on the test request form for easy reference.
Craniosynostosis
Gene Panel
The Human Genetics Laboratory offers
a panel designed to detect aberrations
in four genes known to be associated
with craniosynostosis, the premature
closure of one or more sutures in an
individual’s skull. With an incidence of
1 in every 2,000-2,500 births, many
craniosynostosis syndromes exist and
often have additional clinical features,
making a single panel for the evaluation
of these various syndromes ideal for both
the clinician and the patient.1 Additionally,
aberrations in these genes can inhibit
or alter bone growth; therefore, several
skeletal dysplasias are also covered by
this panel.
SUSPECTED SYNDROMES:
• Achondroplasia
• Antley-Bixler syndrome
COMPREHENSIVE TESTING EXAMPLE
• Apert syndrome
Connective Tissue Disorders Panel
• Beare-Stevenson syndrome
p
 Comprehensive testing [includes: seq, reflex to del/dup]
p Sequencing only
p Del/dup only
Alternatively, individual tests, such as sequencing only or high resolution
deletion/duplication analysis only, can be selected easily on the test
request form, as indicated below.
• CATSHL (tall stature, hearing loss)
• Crouzon syndrome
• Hypochondroplasia
• Jackson-Weiss syndrome
• Kallmann syndrome
• LADD
SINGLE TESTING EXAMPLE
• Muenke syndrome
Connective Tissue Disorders Panel
• Pfeiffer syndrome
p Comprehensive testing [includes: seq, reflex to del/dup]
p Sequencing only
 Del/dup only
p
• Rhizomelic limb shortening
• Radioulnar synostosis
• Robinow-Sorauf syndrome
• Saethre-Chotzen syndrome
Please contact the laboratory if you have any questions about this new
test offering or the updated postnatal test request form.
Newsletter | 6
Connective Tissue Disorders
Gene Panel
Individuals with inherited connective tissue disorders frequently
harbor an aberration in a gene involved in the structure or
function of connective tissue. Such disorders typically include
medical issues with the joints, eyes, skin, and cardiovascular
system, though other body systems are commonly affected.
Often, genetic testing is useful for the establishment of an
appropriate diagnosis and medical management plan for an
affected individual or family. To aid in the diagnosis of patients
with connective tissue disorders, the Human Genetics Laboratory
launched an indication-specific gene panel in the fall of 2013.
CLINICAL INDICATIONS FOR TESTING:
 Craniosynostosis
 Facial features such as proptosis (bulging eyes),
ptosis, widely spaced eyes, flattened midface,
temporal bossing
 Syndactyly, clinodactyly, broad toes, broad thumbs
 Short stature or shortened long bones
 Palatal abnormalities (cleft or high palate)
 Bone fusions, especially carpal, tarsal, and
radioulnar synostosis
 Developmental delay, hearing loss, or vision
concerns in a person suspected to have
craniosynostosis or skeletal dysplasia
GENES COVERED2:
FGFR1 5% Pfeiffer syndrome type 1
100% Apert syndrome
<100% Beare-Stevenson syndrome
100% Crouzon syndrome
FGFR2 100% Jackson-Weiss syndrome
95% Pfeiffer syndrome type 1
100% Pfeiffer syndrome types 2 and 3
100% FGFR2-related isolated coronal synostosis
FGFR3
TWIST
Our laboratory is pleased to announce that as of June 1, 2014,
the connective tissue disorders panel has been expanded to
include a total of 33 clinically useful genes.
CLINICAL INDICATIONS FOR TESTING:
 Joint issues: hypermobility, dislocations, chronic pain
 Skin findings: cutis laxa, abnormal or atrophic scars, poor wound healing,
spontaneous bruising
 Ocular findings: ectopia lentis, myopia, retinal detachment
 Pneumothorax
 Cardiac findings: congenital heart defect, mitral valve prolapse, aortic
root enlargement, thoracic aneurysm, aortic dissection, other aneurysms/
dissections
 Skeletal variants: Tall or short stature, pectus excavatum, pectus
carinatum, arachnodactyly, brachydactyly, pes planus, long wingspan
 Personal or family history of sudden cardiac death, aneurysm/dissection,
rupture of internal organ, rectal or uterine prolapse
 Craniofacial anomalies or dysmorphic features
SUSPECTED SYNDROMES:
• Arterial tortuosity syndrome
• Congenital contractural arachnodactyly
(Beals syndrome)
• Ehlers-Danlos syndrome (all subtypes)
• ELN-related conditions:
>50% Saethre-Chotzen syndrome
1 Greenwood, Jaclyn, Pamela Flodman, Kathryn Osann, Simeon A. Boyadjiev, and Virginia Kimonis.
“Familial Incidence and Associated Symptoms in a Population of Individuals with Nonsyndromic
Craniosynostosis.” Genetics in Medicine (September 26, 2013). doi:10.1038/gim.2013.134.
2 Robin, Nathaniel H, Falk, Marni J, and Haldeman-Englert, Chad R. "FGFR-Related
Craniosynostosis Syndromes". In GeneReviewsTM, edited by Roberta A Pagon, Margaret P Adam,
Thomas D Bird, Cynthia R Dolan, Chin-To Fong, and Karen Stephens. Seattle (WA): University of
Washington, Seattle, 1993. http://www.ncbi.nlm.nih.gov/books/NBK1455/.
FBN1
FBN2
ATP7A
FKBP14
CBS
FLNA
CHST14
MYH11
COL1A1
MYLK
COL1A2
PLOD1
COL2A1
SKI
-- Marfan syndrome
-- MASS phenotype
-- Weill-Marchesani syndrome
-- Isolated ectopia lentis
COL3A1
SLC2A10
COL5A1
SLC39A13
COL5A2
SMAD3
FLNA-related cardiac valvular disease
Homocystinuria
Loeys-Dietz syndrome, types I, II, III, IV
Myhre syndrome
Shprintzen-Goldberg syndrome
Stickler syndrome, types I, II, III, IV, V
COL9A1
SMAD4
COL9A2
TGFB2
COL9A3
TGFBR1
COL11A1
TGFBR2
COL11A2
TNXB
• Familial thoracic aneurysms and aortic
dissections (TAAD)
• FBN1-related disorders
•
•
•
•
•
•
ABCC6
ACTA2
-- Autosomal dominant supravalvular aortic stenosis
-- Cutis laxa
100% Crouzon syndrome with acanthosis nigricans
100% Muenke syndrome
GENE LIST:
ELN
Human Genetics Laboratory Newsletter | Summer 2014